Status and phase
Conditions
Treatments
Study type
Funder types
Identifiers
About
This phase I trial studies the side effects and best dose of sunitinib malate when given together with hydroxychloroquine in treating patients with advanced solid tumors that have not responded to chemotherapy. Sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Hydroxychloroquine may help sunitinib malate work better in treating solid tumors. Giving sunitinib malate together with hydroxychloroquine may kill more tumor cells.
Full description
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of the combination of sunitinib (sunitinib malate) (Sutent), an oral tyrosine kinase inhibitor with antiangiogenic activity that inhibits vascular endothelial growth factor receptor 2 (VEGFR2), stem cell factor receptor (c-kit) and platelet derived growth factor receptor (PDGFR), in combination with hydroxychloroquine (HCQ), an inhibitor of autophagy, in patients with advanced solid tumors that are refractory to standard chemotherapy.
SECONDARY OBJECTIVES:
I. Evaluating blocks of tissue from pre-treatment diagnostic biopsies and tissue from biopsies taken during therapy, when available from enrolled patients, for expression of markers beclin1, light chain 3 (LC3), sequestosome 1 (p62) and hypoxia up-regulated 1 (GRp170) as indicators of autophagy potential.
II. Evaluating pre- and post- treatment peripheral blood mononuclear cells (PBMC) and tumor tissue, when available, for the presence of autophagosomes by electron microscopy (EM) as indication of flux through the autophagy pathway.
III. Evaluating pre- and post- treatment PBMC for changes in the expression of LC3, p62 and GRp170 with the use of single agent sunitinib and the use of the combination of sunitinib with hydroxychloroquine.
IV. Evaluating circulating tumor cells (CTCs) pre- and post- treatment with single agent sunitinib and sunitinib + HCQ, and characterize these for markers of autophagy. (exploratory) V. To determine whether the steady-state plasma concentration of HCQ correlates with inhibition of autophagy and whether a pharmacokinetic interaction exists between sunitinib and HCQ.
VI. To examine, when available, post treatment tumor biopsies for vascular markers to detect decreased vascular proliferation by staining cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF), thrombospondin-1, and cluster of differentiation 105 (CD105) staining to monitor micro vessel density.
OUTLINE: This is a dose-escalation study of hydroxychloroquine.
Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28 and hydroxychloroquine PO once daily (QD) or twice daily (BID) on days 1-42 (beginning day 4 of course 1). Treatment repeats every 42 days for 6 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 6 months.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Patients with histologically or cytologically proven advanced cancer
Patients must have undergone treatment with at least one regimen of standard therapy, either cytotoxic chemotherapy, an oral targeted agent or immunotherapy, or have a form of cancer for which no standard therapy exists, or are not eligible for or decline standard therapy; patients who have received prior therapy with sunitinib will be allowed; patients with prostate cancer may continue on hormonal therapy if they are currently receiving it
Patients must have measurable or evaluable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Life expectancy > 12 weeks
Eastern Cooperative Oncology Group (ECOG) performance status =< 1
Leukocytes >= 3,000/mcL
Absolute neutrophil count >= 1,500/mcL
Platelets >= 100,000/mcL
Hemoglobin >= 9 g/dL
Serum calcium =< 12.0 mg/dL
Total serum bilirubin within normal institutional limits
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/ananine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal, unless the patient has liver metastases, in which case both AST and ALT must be =<5 X institutional upper limit of normal
Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
Thyroid-stimulating hormone (TSH) within normal institutional limits is required for eligibility; free T3 and free T4 values will also be obtained for baseline values should repeat parameters be required later in the course of treatment, however these values will not be used to determine eligibility
Creatine phosphokinase (CPK) within normal institutional limits
The following groups of patients are eligible provided they have New York Heart Association class II (NYHA) cardiac function on baseline echocardiogram (ECHO)/multi gated acquisition scan (MUGA):
Patients who require use of therapeutic doses of Coumadin-derivative anticoagulants such as warfarin are excluded, although doses of up to 2 mg daily are permitted for prophylaxis of thrombosis; note: low molecular weight heparin is permitted provided the patient's prothrombin time (PT) international normalized ratio (INR) is =< 1.5
Ejection fraction measured within institutional limits of normal by MUGA scan
Patients with known brain metastases should be excluded because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
Women must: Have a negative serum or urine pregnancy test within 7 days prior to study entry if she is a woman of child-bearing potential (WOCBP), OR
Patients of childbearing or child fathering potential must be willing to use an acceptable method of birth control prior to study entry and for the duration of the study; acceptable methods of contraception include hormonal, barrier methods, intrauterine device, tubal ligation/vasectomy or abstinence; women should not breast feed while on treatment with sunitinib and HCQ
Patients must not have a history of any condition (social or medical) that, in the opinion of the investigator, might interfere with the patient's ability to comply with the protocol or pose additional or unacceptable risk to the patient
Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain sunitinib tablets are excluded
Approval for HCQ treatment by an eye doctor, based on a screening eye exam; examples of disqualifying baseline conditions include macular degeneration and other retinal disease, see exclusion criteria
Patients must be able to understand and sign informed consent
Exclusion criteria
Primary purpose
Allocation
Interventional model
Masking
40 participants in 1 patient group
Loading...
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal